Immunoglobulin preparation and storage system for an immunoglobulin preparation

ABSTRACT

The present invention relates to an immunoglobulin preparation comprising immunoglobulin in a mass-volume percentage of at least 4%, wherein the concentration of oxygen dissolved in the preparation at room temperature is less than 40 μmol/l.

The present invention relates to an immunoglobulin (Ig) preparation withimproved stability for storage.

The invention further relates to a storage system for the Igpreparation, to a process for providing such a storage system and to theuse of a gas having an oxygen content of less than 20 vol-% forincreasing the storage stability of an Ig preparation.

Ig preparations for Ig replacement therapy, e.g. for the treatment ofprimary immunodeficiency (PID) disorders, such as common variableimmunodeficiency (CVID) and X-linked agammaglobulinemia, are widelyknown in the art. Such Ig preparations are commonly obtained from humanplasma and are stored in vials for further use. The preparation can thenbe administered intravenously (IVIg) or subcutaneously (SCIg) to thepatient in need of the therapy.

When using the subcutaneous route, Ig preparations having a relativelyhigh Ig concentration are desirable, since they allow for a lessfrequent administration and/or an administration of smaller volumes thana preparation of lower concentration.

If stored over several months, known Ig preparations tend to becomeyellowish in colour. This effect is particularly pronounced for Igpreparations having a relatively high Ig concentration and exposed tostress conditions like light exposure and/or elevated temperature; saidpreparations typically show a relatively strong, yellow-brownishcoloration already after storage of two months.

Such a coloration is however in conflict to standard requirements for Igpreparations. The European Pharmacopoeia, for example, requires thepreparation to remain clear-yellow or light brown.

One possible approach to cope with this problem is to store the Igpreparation in a dark environment. A further approach is to store the Igpreparation at a relatively low temperature, for example at about 5° C.Although both approaches have shown to result in a reduction ofyellowish coloration, they are inconvenient for the handling and arerelatively burdensome to put into practice, since the respectiveenvironment has to be maintained over the whole storage period.

It is therefore an object of the present invention to provide an Igpreparation for Ig replacement therapy, which shows a reduced yellowishcoloration and thus allows for complying with the standard requirementsconcerning coloration even after prolonged storage under light and underroom temperature. It is a further object to provide a storage system forstoring the preparation in a manner such that the yellowish colorationis reduced, thus allowing for complying with the standard requirementsconcerning coloration even after prolonged storage under stressconditions like exposure to light and/or elevated temperature.

The problem is solved by the Ig preparation and the storage systemaccording to the independent claims. Preferred embodiments are subjectof the dependent claims.

According to a first aspect, the present invention thus relates to an Igpreparation comprising Ig in a mass-volume percentage of at least 4%(i.e. 4 g/100 ml). In contrast to naturally occurring biological fluids,the liquid Ig preparation of the present invention is thus enriched inIg. Given its relatively high Ig concentration, the preparation issuitable for Ig replacement therapy. Preparations of 10% or more aresuitable for subcutaneous administration which may be performed by thepatients themselves.

It has surprisingly been found that if the concentration of oxygendissolved in the preparation at room temperature is less than 200μmol/l, a high stability against yellowish coloration over a prolongedperiod of time can be achieved. Preferably, the yellowish coloration iscaused by stress factors other than light exposure, i.e. occurs in thedark, is not caused by photodegradation. In particular, a stable Igpreparation showing only a slight yellowish coloration or no yellowishcoloration at all can be achieved, thus meeting standard requirements,e.g. of the European Pharmacopoeia, even after a prolonged storageperiod of 24 months, even of 36 months, or longer. In particular, astable Ig preparation meeting the standard requirements can be achieved,even after a prolonged storage period of 24 months, even of 36 months,at room temperature in the dark. The absorbance A_(350-500 nm) of thestable immunoglobulin preparation remains below 0.28 upon storage for 24months at 25° C. in the dark, preferably the stable immunoglobulinpreparation has a concentration of 20% w/v. In a preferred embodiment ofthe invention, the absorbance A_(350-500 nm) remains below 0.355 whenmeasured for a 20% Ig preparation after storage for 6 months at 37° C.in the dark. The stable immunoglobulin preparation shows an increase inA_(350-500 nm) of less than 0.18, preferably of less than 0.17, evenmore preferably of less than 0.16, when stored at 25° C. in the dark for36 months. The stable immunoglobulin preparation shows an increase inA_(350-500 nm) of less than 0.22, preferably of less than 0.20, evenmore preferably of less than 0.19, when stored at 37° C. in the dark for6 months.

Methods for determining the concentration of oxygen dissolved in the Igpreparation are well known to the skilled person. For example, theoxygen concentration can be determined by a polarographic method, usinge.g. a Clark electrode. Alternatively, also luminescence oxygen sensingcan for example be used for determining the oxygen concentration in thepreparation.

When contained in a container, the Ig preparation's oxygen concentrationcan be determined using an electrode extending into the container andinto the Ig preparation contained therein. Alternatively, the Igpreparation's oxygen concentration can be determined after opening ofthe container. In this latter case, determination is carried out within5 minutes after opening of the container in order to avoid corruption ofthe respective result by an increase of the oxygen content of the gaswhich is in contact with the immunoglobulin preparation.

Without wanting to be bound by the theory, it is assumed that theyellowish coloration typically seen with conventional Ig preparations isdue to an oxidative alteration of the Ig contained therein. According tothe present invention, this oxidative alteration is reduced bymaintaining the amount of oxygen dissolved in the preparation at aconcentration lower than the concentration that would be established ifthe preparation is stored under air at atmospheric pressure.

Given the fact that according to the present invention an Ig preparationcan be obtained, which even after prolonged storage shows only a slightyellowish coloration or no yellowish coloration at all, both patientsand physicians can readily acknowledge that the Ig contained therein isin good quality, which further contributes to an increase in theacceptance of the preparation.

Apart from being indicative for a low degree of presumably oxidative Igalteration, a colourless or only slightly coloured preparation isvisually much more appealing than a yellow or a yellow-brownish one.

A particularly high stability of the Ig preparation of the presentinvention can be achieved if the concentration of oxygen dissolved atroom temperature is less than 175 μmol/l, preferably less than 150μmol/l, more preferably less than 125 μmol/l, and most preferably lessthan 100 μmol/l.

Since for conventional Ig preparations, the effect of yellowishcoloration is particularly pronounced for preparations having a high Igconcentration, the present invention particularly refers to apreparation comprising Ig in a mass-volume percentage of at least 5%,preferably at least 10%, more preferably at least 12%, more preferablyat least 14%, more preferably at least 16%, more preferably at least18%, and most preferably at least 20%. Preferably, the Ig preparation isa polyclonal Ig preparation, more preferably a polyclonal IgGpreparation.

Compliance of the Ig preparation with the respective colorationrequirements of the European Pharmacopoeia can be determined by therespective method given therein (Ph. Eur. 5.5, 2006, General methods2.2.2 Degree of Coloration of Liquids).

Alternatively, compliance with the coloration requirements can also bedetermined by a spectrophotometric method, the results of which havebeen found to correlate with the results of the method according to theEuropean Pharmacopoeia. Specifically, it has been found that an Igpreparation having a mean optical density A_(350-500 nm) (i.e.absorbance at 350 nm minus absorbance at the reference wavelength 500nm) of less than 0.355 fully complies with the respective requirementsof the European Pharmacopoeia.

When stored over 24 months at 25° C. in the dark, a mean increase of theoptical density (absorbance) A_(350-500 nm) of only about 0.1 can beachieved according to the present invention, when stored over 36 monthsat 25° C. in the dark, a mean increase of the optical density of onlyabout 0.15 can be achieved (corresponding to an approximate monthlyincrease of the absorbance of 0.004). When stored over 3 months at 5° C.under light exposure, a mean increase of the optical densityA_(350-500 nm) of only about 0.04 can be achieved according to thepresent invention (corresponding to an approximate monthly increase ofthe absorbance of 0.01), which is in clear contrast to the mean increasefor an Ig preparation in which the oxygen concentration is not reducedaccording to the present invention, said increase being about 1.2(corresponding to an approximate monthly increase of the absorbance of0.40). Further, when stored over 6 months at 37° C. in the dark, a meanincrease of the optical density A_(350-500 nm) of only about 0.18 can beachieved according to the present invention (corresponding to anapproximate monthly increase of the absorbance of 0.03), which is inclear contrast to the mean increase for an Ig preparation in which theoxygen concentration is not reduced according to the present invention,said increase being about 0.24 (corresponding to an approximate monthlyincrease of the absorbance of 0.04).

The Ig preparations of the present invention can be used both for theintravenous and the subcutaneous administration to a patient, by way ofa non-limiting example for the treatment of PID or CVID. The use for thesubcutaneous administration is however preferred.

Given the high concentration of Ig, the present invention allows smallervolumes of the preparation to be administered to the patient whilemaintaining the efficacy compared to conventionally availablepreparations having a lower Ig concentration.

Since the Ig preparation according to the present invention ispreferably used for the subcutaneous administration to a human, thepresent invention also relates to the use of the Ig preparation for thepreparation of a medicament for subcutaneous administration to a human.As for example reported by S. Misbah et al, Clinical and ExperimentalImmunology, 158 (Suppl. 1); pp. 51-59, there are various advantages ofthe subcutaneous administration of the preparation over the intravenousadministration. In particular, venous access is not required and theneed for premedication with corticosteroids and anti-histamines isreduced.

Also, when using the subcutaneous administration route the marked peakstypically seen with monthly IVIg infusions are dampened and persistentlyelevated Ig levels are obtained leading to a reduction in systemic sideeffects.

Preferably, the Ig comprised in the Ig preparation of the presentinvention essentially consists of IgG, but is in no way limited thereto.According to other preferred embodiments of the preparation of thepresent invention, the Ig comprises or essentially consists of IgM orcomprises or essentially consists of IgA, respectively.

According to another aspect, the present invention further relates to astorage system for an Ig preparation, preferably a polyclonal Igpreparation, said storage system comprising a container having aninterior, a first portion of said interior being occupied by the Igpreparation and the remaining second portion of said interior forming aheadspace and being occupied by a gas, wherein in the gas of theheadspace the content of oxygen is less than 20 vol-%. In the context ofthe present invention, the term “vol-%” has the meaning commonly used inthe technical field and denotes the volume ratio of the respective gascomponent in relation to the total volume of the gas in which it iscontained.

The gas in the headspace of the storage system of the present inventionthus has a reduced oxygen content compared to the surrounding air. Ifstored in such a storage system, the oxygen dissolved in the Igpreparation can thus be kept at a concentration below 200 μmol/l,preferably below 175 μmol/l, more preferably below 150 μmol/l, even morepreferably below 125 μmol/l, and most preferably below 100 μmol/l over aprolonged storage period, and yellowish coloration can be vastly reducedeven if the Ig preparation is stored under light and at roomtemperature.

Methods for determining the oxygen content in the gas of the headspaceare known to a skilled person. For example, the oxygen content can bedetermined by laser absorption spectroscopy, in particular tuneablediode laser absorption spectroscopy, thus eliminating interference ofother components contained in the headspace gas. Specifically, theoxygen content can be determined by means of a device of the typeLaserGas™ II (LaserGas Oy, Finland), whereby the absorption line ofoxygen is scanned by means of a single-mode diode. The absorption oflight by the oxygen molecules is measured by a detector, based on whichthe oxygen content of the headspace gas can be calculated.

It is preferred that in the gas of the headspace the content of oxygenis less than 16 vol-%, preferably less than 12 vol-%, more preferablyless than 10 vol-%, and most preferably less than 7 vol-%. An oxygencontent of less than 7 vol-% has been found to be particularlypreferred, since Ig preparations stored under a respective headspace inthe container has been shown to fully comply with the requirements ofthe European Pharmacopoeia even after a prolonged storage period of 24months or longer, even after a storage period of 36 months or longer,even when stored at 25° C. (in the dark), as will be shown in detailbelow.

According to a very straightforward and thus preferred embodiment, thegas of the headspace is at least approximately at atmospheric pressure.

It is further preferred that in the gas of the headspace the content ofinert gas is more than 80 vol-%, preferably more than 84 vol-%, morepreferably more than 88 vol-%, more preferably more than 90 vol-%, andmost preferably more than 93 vol-%. The inert gas may be e.g. nitrogen,argon, other noble gases or mixtures thereof. Given its availability,nitrogen is preferably used.

It is further preferred that the container of the gas-tight storagesystem comprises a vial, in particular a vial as standardized by DIN/ISO8362-1.

According to a further preferred embodiment, the volume ratio of theheadspace to the Ig preparation ranges from about 0.1:1 to 0.9:1,depending on the vial used. For a 6R vial, for example, the ratio istypically about 0.9:1 whereas for a 20R vial, the ratio is typically atabout 0.1:1.

In particular, the storage system of the invention improves thestability of an Ig preparation after a prolonged storage period of 24months, even of 36 months, at room temperature in the dark. When using a20% Ig preparation as reference, the storage system of the inventionprovides that the absorbance A_(350-500 nm) of the immunoglobulinpreparation remains below 0.28 upon storage for 24 months at 25° C. inthe dark, preferably the absorbance A_(350-500 nm) remains below 0.355when measured for a 20% Ig preparation after storage for 6 months at 37°C. in the dark. The storage system of the invention provides a stableimmunoglobulin preparation showing an increase in A_(350-500 nm) of lessthan 0.18, preferably of less than 0.17, even more preferably of lessthan 0.16, when stored at 25° C. in the dark for 36 months. The storagesystem of the invention provides a stable immunoglobulin preparationshowing an increase in A_(350-500 nm) of less than 0.22, preferably ofless than 0.20, even more preferably of less than 0.19, when stored at37° C. in the dark for 6 months.

According to a further aspect, the present invention also relates to aprocess for providing a storage system for an Ig preparation comprisingthe steps that the Ig preparation is filled into a container and thecontainer is sealed, wherein prior to the sealing the headspace of thecontainer is filled with a gas such that the oxygen content in the gasof the headspace is less than 20 vol-%, preferably less than 16 vol-%,more preferably less than 12 vol-%, even more preferably less than 10vol-%, and most preferably less than 7 vol-%. This “inert gassing” ofthe headspace allows the concentration of the oxygen dissolved to bekept at a concentration below 200 μmol/l preferably below 175 μmol/l,more preferably below 150 μmol/l, even more preferably below 125 μmol/l,and most preferably below 100 μmol/l over a prolonged storage period.Preferably, the prolonged storage period is longer than 24 months,preferably even longer than 36 months, at 25° C. (or room temperature)in the dark. In particular, the process of the invention improves thestability of an Ig preparation after a prolonged storage period of 24months, even of 36 months, at room temperature in the dark. When using a20% Ig preparation as reference, the process of the invention providesthat the absorbance A_(350-500 nm) of the immunoglobulin preparationremains below 0.28 upon storage for 24 months at 25° C. in the dark,preferably the absorbance A_(350-500 nm) remains below 0.355 whenmeasured for a 20% Ig preparation after storage for 6 months at 37° C.in the dark. The process of the invention provides a stableimmunoglobulin preparation showing an increase in A_(350-500 nm) of lessthan 0.18, preferably of less than 0.17, even more preferably of lessthan 0.16, when stored at 25° C. in the dark for 36 months. The processof the invention provides a stable immunoglobulin preparation showing anincrease in A_(350-500 nm) of less than 0.22, preferably of less than0.20, even more preferably of less than 0.19, when stored at 37° C. inthe dark for 6 months.

Preferably, the gas of the headspace of the storage system obtained isat atmospheric pressure.

Alternatively or additionally to the above process, an Ig preparationdefined above with a reduced concentration of oxygen dissolved can beobtained by subjecting the Ig preparation or its solvent to a degassingstep and/or a gassing step using an inert gas. It is thereby preferredthat the solvent of the Ig preparation, typically water, is subjected tothe degassing and/or gassing step prior to the formulation of the Igpreparation. Degassing can for example be obtained by storing thesolvent at an elevated temperature or at a reduced pressure. Gassingusing an inert gas can for example be performed by introducing the inertgas into the respective preparation or its solvent.

In accordance with the above, the present invention relates according toa further aspect also to the use of a gas having an oxygen content ofless than 20 vol-% for increasing the storage stability of animmunoglobulin preparation comprising immunoglobulin in a mass-volumepercentage of at least 4%. As given above, the gas is thereby preferablyused in the headspace of a container in which the Ig preparation isstored.

With the storage system of the invention, or the process of theinvention, or the use of a gas with an oxygen content of less than 20%according to the invention, a reduction in the mean increase ofabsorbance at 350nm for an Ig preparation of at least 10% is achievable,preferably of more than 12%, 14%, 16%, 18% or 20%, more preferably ofmore than 25%, 30%, 35%, 38%, 40%, or even 45% can be achieved whenstored for a prolonged period in the dark. With the storage system orprocess of the invention, this can be achieved for preparationscomprising Ig in a mass-volume percentage of at least 5%, preferably atleast 10%, more preferably at least 12%, more preferably at least 14%,more preferably at least 16%, more preferably at least 18%, and mostpreferably at least 20%.

A detailed description of a process according to the present inventionis given in the example below.

EXAMPLES Ig preparation

The technical effect achieved by the present invention was assessedusing IgPro20.

IgPro20 is a ready-to-use, 20% (200 g/l) liquid preparation ofpolyvalent human IgG for subcutaneous administration, manufactured fromlarge pools of human plasma. Its protein moiety is ≧98% IgG, of whichover 90% is in the form of monomers+dimers. IgPro20 is formulated withthe stabilizer L-proline (250 mmol/L) at pH 4.8 without preservatives.

Filling of the Ig Preparation

During aseptic filling of IgPro20 into a vial, the headspace of the vialwas gassed with nitrogen.

Specifically, gassing with nitrogen was carried out in two steps:

a) directly after introducing the Ig preparation into the vial,sterile-filtered nitrogen gas was filled into the headspace by means ofan inflation needle extending into the headspace;

b) during insertion of the plug for sealing the vial, nitrogen gas wasblown onto the opening of the vial by a further inflation needleextending in angular direction with regard to the axis of the opening.

The nitrogen gas used was sterile-filtered using a sterile filter of thetype KA02PFRP8 of Pall Corporation. The operating pressure of thegassing equipment was set to about 0.5 bar.

By the above procedure, a storage system can be provided having aheadspace which immediately after sealing of the vial has an oxygencontent of less than 4.5 vol-%. Given the fact that the preparation isnot degassed or gassed with an inert gas before filling into the vial,the oxygen content in the gas of the headspace might increase until anequilibrium between the immunoglobulin and the gas is established. Evenin this case, the content of oxygen remains below 7 vol-%.

Storage Conditions

The storage conditions and test intervals of the long-term stabilityprogram for IgPro20 were chosen according to the InternationalConference on Harmonization (ICH) of Technical Requirements forRegistration of Pharmaceuticals for Human Use guideline Q1A(R2).Long-term storage for up to 24 months at 25° C. is shown in FIG. 3below.

In order to simulate secondary packaging, the vials were stored at atemperature of 37° C. in the dark.

A horizontal position of the container maintained contact of thesolution with the stopper, in accordance with ICH guideline Q5C.

Quantification of Yellowish Coloration

In order to quantify yellowing of the Ig preparation, its mean opticaldensity at 350 to 500 nm has been determined after several intervals ofstoring. This is based on the finding that the mean optical density canbe correlated to the standardized examination of the coloration ofliquids as described in the European Pharmacopoeia (Ph. Eur. 5.6,January 2005, General methods 2.2.2, Degree of Coloration of Liquids).

The technical effect achieved by the present invention is illustrated byway of the attached figures, of which

FIG. 1 is a graphical representation of the optical density (absorbance)A_(350-500 nm) of the Ig preparation stored as a function of storagetime after storage at 5° C. under light without inert gassing of theheadspace (diamonds), using a gas in the headspace having an oxygencontent of 16 vol-% (squares), 12 vol-% (triangles), 10 vol-% (crosses),7 vol-% (stars) and less than 7 vol-% (circles), respectively; and

FIG. 2 is a graphical representation of the optical density (absorbance)A_(350-500 nm) of the Ig preparation stored as a function of storagetime after storage at 37° C. in the dark without inert gassing of theheadspace (diamonds) and using a gas in the headspace having an oxygencontent of at most 7 vol-% (squares), respectively, and

FIG. 3 is a graphical representation of the mean optical density(absorbance) A_(350-500 nm) of a number of samples of the Ig preparationas a function of storage time when stored at 25° C. in the dark using agas in the headspace having an oxygen content of less than 7 vol-%.

As can be seen from FIG. 1, yellowing of the immunoglobulin preparationovertime is reduced by using a gas having a reduced oxygen content (andthus also a reduced oxygen partial pressure) in the headspace.Specifically, by using a gas having an oxygen content of less than 7vol-%, the optical density A_(350-500 nm) is less than 0.35 even afterstorage for 6 months, thus fully complying with the requirements of theEuropean Pharmacopoeia after prolonged storage. The concentration ofoxygen dissolved in the respective sample at room temperature is lessthan 100 μmol/l.

Referring to FIG. 2, a mean increase of the optical densityA_(350-500 nm) of only about 0.18 can be achieved according to thepresent invention when stored over 6 months at 37° C. in the dark usinga gas in the headspace having an oxygen content of at most 7 vol-%. Thisis in clear contrast to the mean increase for an Ig preparation storedwithout gassing of the headspace, said increase being about 0.24.

As shown in FIG. 3, a mean increase of the mean optical densityA_(350-500 nm) of only about 0.1 can be achieved according to thepresent invention when stored over 24 months at 25° C. in the dark.

As shown in Table 1 below, the mean optical density is still below 0.355even after storage over 36 months at 25° C. in the dark, and even lowerif stored at 5° C. in the dark. The values of 6 different lots areshown.

TABLE 1 25° C. 5° C. 30 months 36 months 30 months 36 months O₂ O₂ O₂ O₂μmol/L % O₂ A₃₅₀ μmol/L % O₂ A₃₅₀ μmol/L % O₂ A₃₅₀ μmol/L % O₂ A₃₅₀ 79.26.3 0.270 83.5 6.6 0.319 61.3 4.8 0.156 58.4 4.6 0.158 75.8 6.0 0.22979.9 6.3 0.249 56.0 4.4 0.132 54.8 4.3 0.130 82.4 6.5 0.297 86.3 6.80.332 65.3 5.1 0.181 62.4 4.9 0.186 53.3 4.2 0.298 54.3 4.3 0.289 66.05.2 0.155 62.3 4.9 0.159 55.7 4.4 0.231 57.3 4.5 0.244 62.3 4.9 0.13358.5 4.6 0.131 54.7 4.3 0.290 56.3 4.4 0.318 63.5 5.0 0.180 59.8 4.70.179

Table 2 shows the mean monthly increase in absorbance A_(350-500 nm) indifferent storage conditions. For all conditions tested, keeping theoxygen concentration below 100 μmol/l, or below 7% oxygen in theheadspace, leads to significantly lower increase in absorbance,indicating significantly higher stability of the IgG preparation. Allsamples were stored in the dark. Data were collected for 24 or 36months: during this time, the increase of absorbance over time was aboutlinear.

TABLE 2 Mean monthly A_(350-500 nm) Storage Oxygen in increase inreduction temperature headspace A_(350-500 nm) by O2 reduction 37° C.<7% 0.030 42.5% 20% (air) 0.052 25° C. <7% 0.0042 19.9% 20% (air) 0.0052 5° C. <7% 0.00037 47.8% 20% (air) 0.00071

1. Immunoglobulin preparation comprising immunoglobulin in a mass-volumepercentage of at least 4%, wherein the concentration of oxygen dissolvedin the preparation at room temperature is less than 200 μmol/l, whereinthe absorbance. at 350 nm minus the absorbance at 500 nm (absorbanceA_(350-500 nm)) of the immunoglobulin preparation remains below 0.28upon storage for 24 months at 25° C. in the dark.
 2. The immunoglobulinpreparation according to claim 1, wherein the concentration of oxygendissolved in the preparation at room temperature is less than 175μmol/l.
 3. The immunoglobulin preparation according to claim 1, whereinthe immunoglobulin preparation comprises immunoglobulin in a mass-volumepercentage of at least 5%.
 4. The immunoglobulin preparation accordingto claim 1, wherein the immunoglobulin comprised in the immunoglobulinpreparation consists essentially of IgG.
 5. The immunoglobulinpreparation according to claim 1, wherein the preparation has a meanincrease in absorbance A_(350-500 nm) of less than 0.2 upon storage of 6months at 37° C. in the dark.
 6. (canceled)
 7. Storage system for animmunoglobulin preparation comprising a container having an interior, afirst portion of said interior being occupied by the immunoglobulinpreparation according to claim 1, and the remaining portion of saidinterior forming a headspace and being occupied by a gas other than air,wherein the content of oxygen in the gas of the headspace is less than20 vol-%, and wherein the absorbance A_(350-500 nm) of theimmunoglobulin preparation in the container remains below 0.28 uponstorage for 24 months at 25° C. in the dark.
 8. The storage systemaccording to claim 7, wherein the content of oxygen in the gas of theheadspace is less than 16 vol-%.
 9. The storage system according toclaim 7, wherein the gas of the headspace is at approximatelyatmospheric or higher than atmospheric pressure.
 10. The storage systemaccording to claim 7, wherein the content of inert gas in the gas of theheadspace is more than 80 vol-%.
 11. The storage system according toclaim 7, wherein the container is a vial.
 12. The storage systemaccording to claim 7, wherein the headspace and the immunoglobulinpreparation are in a volume ratio that ranges from 0.1:1 to 0.9:1. 13.The storage system according to claim 7, wherein the storage system hasa mean monthly increase of absorbance A_(350-500 nm) that is at least10% lower than the mean monthly increase of absorbance A_(350-500 nm)observed when air is used as the gas in the headspace.
 14. Process forpreparing a storage system for an immunoglobulin preparation, comprisingfilling a container with the immunoglobulin preparation according toclaim 1, filling the container with a gas other than air, and sealingthe container, wherein the gas forms a headspace above the preparation,and wherein the gas of the headspace has an oxygen content of less than20 vol-%.
 15. The process according to claim 14, wherein the gas filledinto the container is at atmospheric pressure.
 16. The process accordingto claim 14, wherein the immunoglobulin preparation comprisesimmunoglobulin in a solvent, and wherein the process comprisessubjecting the immunoglobulin and/or its solvent to a degassing stepand/or a gassing step using an inert gas.
 17. The process according toclaim 16, wherein the solvent is subjected to the degassing and/orgassing step using an inert gas prior to formulation of the preparation.18. (canceled)
 19. A method of treating a primary immunodeficiencydisorder in a patient in need thereof, comprising administering aneffective amount of the immunoglobulin preparation of claim
 1. 20. Theimmunoglobulin preparation according to claim 1, wherein theimmunoglobulin preparation comprises immunoglobulin in a mass-volumepercentage of 14-20%.
 21. The immunoglobulin preparation according toclaim 1, wherein the immunoglobulin preparation comprises immunoglobulinin a mass-volume percentage of at least 18%.
 22. The immunoglobulinpreparation according to claim 1, wherein the immunoglobulin preparationcomprises immunoglobulin in a mass-volume percentage of at least 20%.